Circadian Control of Pancreatic Beta-cell Maturation

胰腺β细胞成熟的昼夜节律控制

• 批准号: 10455667
• 负责人: Juan R Alvarez
• 金额: $ 15.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-22 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455667
• 关键词: Address; Animals; Behavior Therapy; Beta Cell; Binding; Biochemical; Biological; Biological Assay; Birth; Cell Maturation; Cell physiology; Cells; Chromatin; Chronic; Circadian Rhythms; Clinical Research; Complement; Coupled; Defect; Development; Diabetes Mellitus; Diabetic mouse; Enhancers; Ensure; Environment; Exocytosis; Family suidae; Fasting; Fostering; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic study; Genomics; Glucose; Goals; Human; In Vitro; Insulin; Lead; Link; Maintenance; Measures; Mediator of activation protein; Mentors; Metabolic; Methods; Molecular; Morphologic artifacts; Mus; Mutant Strains Mice; Neonatal; Non-Insulin-Dependent Diabetes Mellitus; Periodicity; Phenotype; Physiological; Physiology; Population; Process; Proteins; Proteome; Regulation; Reporter; Research; Research Personnel; Risk; Rodent; Role; Series; Sleep; Specificity; Stimulus; Structure; Structure of beta Cell of islet; Testing; Therapeutic; Training; Training Activity; Transcription Coactivator; Weaning; behavioral pharmacology; career development; circadian; circadian biology; circadian pacemaker; diabetes mellitus genetics; diabetic patient; epidemiology study; epigenome; experience; experimental study; feeding; fetal; glucose tolerance; in utero; innovation; insight; insulin dependent diabetes mellitus onset; insulin secretion; insulin sensitivity; islet; mRNA Expression; novel strategies; postnatal; prevent; programs; promoter; recruit; research and development; response; shift work; single cell technology; skills; stem cells; therapeutic target; therapy development; transcription factor; transcriptome; transplantation therapy

PROJECT SUMMARY/ABSTRACT Following developmental specification, pancreatic beta cells adapt to changes in the postnatal environment through functional maturation. They gain glucose-responsive insulin secretion, and gradually refine it by increasing the glucose threshold for secretion and expanding secretory capacity. While factors promoting beta cell maturation have been described, the underlying molecular mechanisms and their physiological triggers remain unclear. New insights into how beta cells acquire their mature phenotype are needed to develop efforts to curb loss of this phenotype during the onset of type 1 and type 2 diabetes, and to generate functionally mature beta cells from stem cells that can be used as transplantation therapy. The transcription factor Dec1 is a modulator of the circadian clock mechanism that is specifically activated during postnatal beta cell maturation. Dec1 binds promoter/enhancers of genes encoding key mediators of mature glucose sensing and insulin secretion, and loss of Dec1 in beta cells renders mice diabetic due to physiologically immature islets. Dr. Alvarez proposes to investigate the molecular basis for these phenotypes, by 1) examining the impact of Dec1 loss on the epigenome, transcriptome, and proteome of single pancreatic beta cells, and 2) determining the functional partners and molecular mechanisms by which Dec1 modulates beta cell maturity. These innovative experiments complement Dr. Alvarez' prior skills while conferring new training in circadian live-animal studies and single-cell technologies. A world-class team of mentors and collaborators with leading experience in these methods and in beta cell, diabetes, and circadian physiology ensures exceptional guidance. In addition, a series of formal, structured didactic and experiential training activities aimed at fostering Dr. Alvarez' development as an independent investigator are proposed. In all, the proposed research and career development activities will be critical to Dr. Alvarez developing a new independent research program focused on linking circadian biology to beta cell physiology. Results from this research program will be important to identify and exploit therapeutic opportunities to manage, prevent, or even restore the loss of mature beta cell function in diabetic patients.

项目摘要/摘要 遵循发育规范，胰腺β细胞适应产后环境的变化 通过功能成熟。他们获得葡萄糖响应性胰岛素分泌，并通过 增加葡萄糖阈值以扩大分泌能力。而促进Beta的因素 已经描述了细胞成熟，即潜在的分子机制及其生理触发因素 保持不清楚。关于β细胞如何获得成熟表型的新见解以开发努力 在1型和2型糖尿病的发作期间抑制这种表型的丧失，并在功能上产生 来自干细胞的成熟β细胞可用作移植疗法。 转录因子DEC1是昼夜节律机制的调节器，该机制被专门激活 在产后β细胞成熟期间。 DEC1结合编码基因的启动子/增强子，编码的关键介体 成熟的葡萄糖感应和胰岛素分泌，以及β细胞中DEC1的丧失使小鼠糖尿病 生理上不成熟的小岛。 Alvarez博士建议研究这些表型的分子基础， 1）检查DEC1损失对单个胰腺的表观基因组，转录组和蛋白质组的影响 β细胞和2）确定功能伙伴和分子机制调节DEC1 β细胞成熟度。 这些创新的实验补充了阿尔瓦雷斯博士的先前技能，同时授予昼夜节律的新培训 实时研究和单细胞技术。一个世界一流的导师团队和合作者 在这些方法和β细胞，糖尿病和昼夜节律生理学中的经验可确保出色 指导。此外，一系列针对 提出了促进阿尔瓦雷斯博士作为独立研究者的发展。 总的来说，拟议的研究和职业发展活动对于阿尔瓦雷斯博士开发新的新活动至关重要 独立研究计划的重点是将昼夜节律生物学与β细胞生理联系起来。结果 研究计划对于识别和利用治疗机会来管理，预防或什至很重要 恢复糖尿病患者成熟β细胞功能的丧失。